aInstitute of Biomedical StudiesbDepartment of Psychology and NeurosciencecDepartment of Biology, Baylor University, WacodTexas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TexaseDepartment of Neurosurgery, David Geffen School of Medicine, The UCLA Brain Injury Research Center, University of California at Los Angeles, Los Angeles, CaliforniafDepartment of Psychology and Interdepartmental Neuroscience Program, Northwestern University, Evanston, Illinois, USA

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Abstract

Dysregulation of the PI3K/Akt/mTOR signaling cascade has been associated with the pathology of neurodegenerative disorders, specifically Alzheimer’s disease (AD). Both in-vivo models and post-mortem brain samples of individuals with AD have commonly shown hyperactivation of the pathway. In the present study, we examine how neuron subset-specific deletion of Pten (NS-Pten) in mice, which presents with hyperactive mammalian target of rapamycin (mTOR) activity, affects the hippocampal protein levels of key neuropathological hallmarks of AD. We found NS-Pten knockout (KO) mice to have elevated levels of amyloid-β, α-synuclein, neurofilament-L, and pGSK3α in the hippocampal synaptosome compared with NS-Pten wild type mice. In contrast, there was a decreased expression of amyloid precursor protein, tau, GSK3α, and GSK3β in NS-Pten KO hippocampi. Overall, there were significant alterations in levels of proteins associated with AD pathology in NS-Pten KO mice. This study provides novel insight into how altered mTOR signaling is linked to AD pathology, without the use of an in-vivo AD model that already displays neuropathological hallmarks of the disease.